Up to 30% of low birth weight preterm infants manifest some form of periventricular white matter injury (PWMI), making it the most common form of brain injury affecting premature infants. In the US, 150,000 infants per year are born at risk for PWMI, and about 25,000 children per year will develop PWMI. World-wide, 1,000,000 infants will be born each year at risk for PWMI, and about 250,000 children per year will develop PWMI. Oligodendrocytes (OLs) are the myelinating cells of the central nervous system and play a critical role in white matter formation. It is believed that loss and impaired differentiation of Pre-oligodendrocytes (PreOLs), which are proliferative cells that develop into myelinating OLs, plays a major role in PWMI causation. Presently, there are few pharmacological approaches that specifically target PreOLs, resulting in increased proliferation of these cells and increased brain myelination. To address this short coming, Dr. Scott Rivkees (University of Florida) used high-throughput screening to identify compounds that would stimulate PreOL proliferation. These initial studies of 25,000 compounds identified diazoxide as a stimulator of PreOL proliferation, and showed that this compound promotes myelination in a murine model of PWMI. However, diazoxide was not completely effective in preventing PWMI, leading us to look for other compounds that are potentially even more effective than diazoxide. Dr. Rivkees thus developed 610 small molecule derivatives of diazoxide that were tested for their ability stimulates the proliferation of PreOLs. These studies identified 25 compounds that stimulated PreOL proliferation, 4 of which (designated lead compounds) were significantly more potent than diazoxide. Medosome Biotec, LLC, a Florida-based small business, and its research partner at the University of Florida (Dr. Rivkees) postulate these lead compounds have the potential to be effective new therapeutics for disorders of myelination. In these Phase I STTR studies, the team proposes to assess the toxicity and myelination potential of our lead compounds. We will: 1. Evaluate myelination in brain slices 2. Assess in vivo toxicology and myelination potential The long-term goal of this work is to develop and commercialize novel therapeutic agents for the treatment of white matter injury in premature infants and other disorders of myelination. This STTR award will link scientists at Medosome LLC and Dr. Rivkees (University of Florida), who is a leading expert in the area of white matter injury.